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Open Access 01-12-2017 | Research article

Genetic polymorphisms in key hypoxia-regulated downstream molecules and phenotypic correlation in prostate cancer

Authors: Avelino Fraga, Ricardo Ribeiro, André Coelho, José Ramon Vizcaíno, Helena Coutinho, José Manuel Lopes, Paulo Príncipe, Carlos Lobato, Carlos Lopes, Rui Medeiros

Published in: BMC Urology | Issue 1/2017

Abstract

Background

In this study we sought if, in their quest to handle hypoxia, prostate tumors express target hypoxia-associated molecules and their correlation with putative functional genetic polymorphisms.

Methods

Representative areas of prostate carcinoma (n = 51) and of nodular prostate hyperplasia (n = 20) were analysed for hypoxia-inducible factor 1 alpha (HIF-1α), carbonic anhydrase IX (CAIX), lysyl oxidase (LOX) and vascular endothelial growth factor (VEGFR2) immunohistochemistry expression using a tissue microarray. DNA was isolated from peripheral blood and used to genotype functional polymorphisms at the corresponding genes (HIF1A +1772 C > T, rs11549465; CA9 + 201 A > G; rs2071676; LOX +473 G > A, rs1800449; KDR – 604 T > C, rs2071559).

Results

Immunohistochemistry analyses disclosed predominance of positive CAIX and VEGFR2 expression in epithelial cells of prostate carcinomas compared to nodular prostate hyperplasia (P = 0.043 and P = 0.035, respectively). In addition, the VEGFR2 expression score in prostate epithelial cells was higher in organ-confined and extra prostatic carcinoma compared to nodular prostate hyperplasia (P = 0.031 and P = 0.004, respectively). Notably, for LOX protein the immunoreactivity score was significantly higher in organ-confined carcinomas compared to nodular prostate hyperplasia (P = 0.015). The genotype-phenotype analyses showed higher LOX staining intensity for carriers of the homozygous LOX +473 G-allele (P = 0.011). Still, carriers of the KDR−604 T-allele were more prone to have higher VEGFR2 expression in prostate epithelial cells (P < 0.006).

Conclusions

Protein expression of hypoxia markers (VEGFR2, CAIX and LOX) on prostate epithelial cells was different between malignant and benign prostate disease. Two genetic polymorphisms (LOX +473 G > A and KDR−604 T > C) were correlated with protein level, accounting for a potential gene-environment effect in the activation of hypoxia-driven pathways in prostate carcinoma. Further research in larger series is warranted to validate present findings.

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Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMed

Wiklund F. Prostate cancer genomics: can we distinguish between indolent and fatal disease using genetic markers? Genome Med. 2010;2(7):45.CrossRefPubMedPubMedCentral

Fraga A, Ribeiro R, Medeiros R. Tumor hypoxia: the role of HIF. Actas Urol Esp. 2009;33(9):941–51.CrossRefPubMed

Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 2006;441(7092):437–43.CrossRefPubMed

Harris AL. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2(1):38–47.CrossRefPubMed

Brahimi-Horn MC, Pouyssegur J. The hypoxia-inducible factor and tumor progression along the angiogenic pathway. Int Rev Cytol. 2005;242:157–213.CrossRefPubMed

Stewart GD, Gray K, Pennington CJ, Edwards DR, Riddick AC, Ross JA, Habib FK. Analysis of hypoxia-associated gene expression in prostate cancer: lysyl oxidase and glucose transporter-1 expression correlate with Gleason score. Oncol Rep. 2008;20(6):1561–7.PubMed

Gupta S, Srivastava M, Ahmad N, Bostwick DG, Mukhtar H. Over-expression of cyclooxygenase-2 in human prostate adenocarcinoma. Prostate. 2000;42(1):73–8.CrossRefPubMed

Baltaci S, Orhan D, Gogus C, Turkolmez K, Tulunay O, Gogus O. Inducible nitric oxide synthase expression in benign prostatic hyperplasia, low- and high-grade prostatic intraepithelial neoplasia and prostatic carcinoma. BJU Int. 2001;88(1):100–3.CrossRefPubMed

10.

Vergis R, Corbishley CM, Norman AR, Bartlett J, Jhavar S, Borre M, Heeboll S, Horwich A, Huddart R, Khoo V, et al. Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment: a retrospective analysis of two randomised radiotherapy trials and one surgical cohort study. Lancet Oncol. 2008;9(4):342–51.CrossRefPubMed

11.

Teixeira AL, Ribeiro R, Morais A, Lobo F, Fraga A, Pina F, Calais-da-Silva FM, Calais-da-Silva FE, Medeiros R. Combined analysis of EGF + 61G > A and TGFB1 + 869T > C functional polymorphisms in the time to androgen independence and prostate cancer susceptibility. Pharmacogenomics J. 2009;9(5):341–6.CrossRefPubMed

12.

Ribeiro RJ, Monteiro CP, Azevedo AS, Cunha VF, Ramanakumar AV, Fraga AM, Pina FM, Lopes CM, Medeiros RM, Franco EL. Performance of an adipokine pathway-based multilocus genetic risk score for prostate cancer risk prediction. PLoS ONE. 2012;7(6), e39236.CrossRefPubMedPubMedCentral

13.

Fraga A, Ribeiro R, Principe P, Lobato C, Pina F, Mauricio J, Monteiro C, Sousa H, CalaisdaSilva F, Lopes C, et al. The HIF1A functional genetic polymorphism at locus +1772 associates with progression to metastatic prostate cancer and refractoriness to hormonal castration. Eur J Cancer. 2014;50(2):359–65.CrossRefPubMed

14.

Vainrib M, Golan M, Amir S, Dang DT, Dang LH, Bar-Shira A, Orr-Urtreger A, Matzkin H, Mabjeesh NJ. HIF1A C1772T polymorphism leads to HIF-1alpha mRNA overexpression in prostate cancer patients. Cancer Biol Ther. 2012;13(9):720–6.CrossRefPubMed

15.

Ye Y, Wang M, Hu S, Shi Y, Zhang X, Zhou Y, Zhao C, Wang G, Wen J, Zong H. Hypoxia-inducible factor-1alpha C1772T polymorphism and cancer risk: a meta-analysis including 18,334 subjects. Cancer Investig. 2014;32(4):126–35.CrossRef

16.

Foley R, Marignol L, Thomas AZ, Cullen IM, Perry AS, Tewari P, O’Grady A, Kay E, Dunne B, Loftus B, et al. The HIF-1alpha C1772T polymorphism may be associated with susceptibility to clinically localised prostate cancer but not with elevated expression of hypoxic biomarkers. Cancer Biol Ther. 2009;8(2):118–24.CrossRefPubMed

17.

Chau CH, Permenter MG, Steinberg SM, Retter AS, Dahut WL, Price DK, Figg WD. Polymorphism in the hypoxia-inducible factor 1alpha gene may confer susceptibility to androgen-independent prostate cancer. Cancer Biol Ther. 2005;4(11):1222–5.CrossRefPubMed

18.

Fu XS, Choi E, Bubley GJ, Balk SP. Identification of hypoxia-inducible factor-1alpha (HIF-1alpha) polymorphism as a mutation in prostate cancer that prevents normoxia-induced degradation. Prostate. 2005;63(3):215–21.CrossRefPubMed

19.

Li P, Cao Q, Shao PF, Cai HZ, Zhou H, Chen JW, Qin C, Zhang ZD, Ju XB, Yin CJ. Genetic polymorphisms in HIF1A are associated with prostate cancer risk in a Chinese population. Asian J Androl. 2012;14(6):864–9.CrossRefPubMedPubMedCentral

20.

Li H, Bubley GJ, Balk SP, Gaziano JM, Pollak M, Stampfer MJ, Ma J. Hypoxia-inducible factor-1alpha (HIF-1alpha) gene polymorphisms, circulating insulin-like growth factor binding protein (IGFBP)-3 levels and prostate cancer. Prostate. 2007;67(12):1354–61.CrossRefPubMed

21.

Ranasinghe WK, Baldwin GS, Bolton D, Shulkes A, Ischia J, Patel O. HIF1alpha expression under normoxia in prostate cancer: which pathways to target? J Urol. 2014;193:763–70.CrossRefPubMed

22.

Zhao T, Lv J, Zhao J, Nzekebaloudou M. Hypoxia-inducible factor-1alpha gene polymorphisms and cancer risk: a meta-analysis. J Exp Clin Cancer Res. 2009;28:159.CrossRefPubMedPubMedCentral

23.

Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, Mason M, Matveev V, Wiegel T, Zattoni F, et al. EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol. 2014;65(1):124–37.CrossRefPubMed

24.

Pertega-Gomes N, Vizcaino JR, Miranda-Goncalves V, Pinheiro C, Silva J, Pereira H, Monteiro P, Henrique RM, Reis RM, Lopes C, et al. Monocarboxylate transporter 4 (MCT4) and CD147 overexpression is associated with poor prognosis in prostate cancer. BMC Cancer. 2011;11:312.CrossRefPubMedPubMedCentral

25.

Holzer TR, Fulford AD, Nedderman DM, Umberger TS, Hozak RR, Joshi A, Melemed SA, Benjamin LE, Plowman GD, Schade AE, et al. Tumor cell expression of vascular endothelial growth factor receptor 2 is an adverse prognostic factor in patients with squamous cell carcinoma of the lung. PLoS ONE. 2013;8(11), e80292.CrossRefPubMedPubMedCentral

26.

Smyth LG, O’Hurley G, O’Grady A, Fitzpatrick JM, Kay E, Watson RW. Carbonic anhydrase IX expression in prostate cancer. Prostate Cancer Prostatic Dis. 2010;13(2):178–81.CrossRefPubMed

27.

Albinger-Hegyi A, Stoeckli SJ, Schmid S, Storz M, Iotzova G, Probst-Hensch NM, Rehrauer H, Tinguely M, Moch H, Hegyi I. Lysyl oxidase expression is an independent marker of prognosis and a predictor of lymph node metastasis in oral and oropharyngeal squamous cell carcinoma (OSCC). Int J Cancer J International du cancer. 2010;126(11):2653–62.

28.

Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148(3):399–408.CrossRefPubMedPubMedCentral

29.

Zhong H, Agani F, Baccala AA, Laughner E, Rioseco-Camacho N, Isaacs WB, Simons JW, Semenza GL. Increased expression of hypoxia inducible factor-1alpha in rat and human prostate cancer. Cancer Res. 1998;58(23):5280–4.PubMed

30.

Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999;59(22):5830–5.PubMed

31.

Saramaki OR, Savinainen KJ, Nupponen NN, Bratt O, Visakorpi T. Amplification of hypoxia-inducible factor 1alpha gene in prostate cancer. Cancer Genet Cytogenet. 2001;128(1):31–4.CrossRefPubMed

32.

Ranasinghe WK, Xiao L, Kovac S, Chang M, Michiels C, Bolton D, Shulkes A, Baldwin GS, Patel O. The role of hypoxia-inducible factor 1alpha in determining the properties of castrate-resistant prostate cancers. PLoS ONE. 2013;8(1), e54251.CrossRefPubMedPubMedCentral

33.

Bos R, Zhong H, Hanrahan CF, Mommers EC, Semenza GL, Pinedo HM, Abeloff MD, Simons JW, Van Diest PJ, van der Wall E. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst. 2001;93(4):309–14.CrossRefPubMed

34.

Birner P, Schindl M, Obermair A, Breitenecker G, Oberhuber G. Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy. Clin Cancer Res. 2001;7(6):1661–8.PubMed

35.

Aebersold DM, Burri P, Beer KT, Laissue J, Djonov V, Greiner RH, Semenza GL. Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res. 2001;61(7):2911–6.PubMed

36.

Waldner MJ, Wirtz S, Jefremow A, Warntjen M, Neufert C, Atreya R, Becker C, Weigmann B, Vieth M, Rose-John S, et al. VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer. J Exp Med. 2010;207(13):2855–68.CrossRefPubMedPubMedCentral

37.

Kroll J, Waltenberger J. The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. J Biol Chem. 1997;272(51):32521–7.CrossRefPubMed

38.

Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, Ferrara N. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem. 1998;273(46):30336–43.CrossRefPubMed

39.

Saraswati S, Kumar S, Alhaider AA. alpha-santalol inhibits the angiogenesis and growth of human prostate tumor growth by targeting vascular endothelial growth factor receptor 2-mediated AKT/mTOR/P70S6K signaling pathway. Mol Cancer. 2013;12:147.CrossRefPubMedPubMedCentral

40.

Hahn D, Simak R, Steiner GE, Handisurya A, Susani M, Marberger M. Expression of the VEGF-receptor Flt-1 in benign, premalignant and malignant prostate tissues. J Urol. 2000;164(2):506–10.CrossRefPubMed

41.

Ferrer FA, Miller LJ, Lindquist R, Kowalczyk P, Laudone VP, Albertsen PC, Kreutzer DL. Expression of vascular endothelial growth factor receptors in human prostate cancer. Urology. 1999;54(3):567–72.CrossRefPubMed

42.

Pallares J, Rojo F, Iriarte J, Morote J, Armadans LI, De Torres I. Study of microvessel density and the expression of the angiogenic factors VEGF, bFGF and the receptors Flt-1 and FLK-1 in benign, premalignant and malignant prostate tissues. Histol Histopathol. 2006;21(8):857–65.PubMed

43.

Bai AS, Zeng H, Li X, Wei Q, Li H, Yang YR. Expression of kinase insert domain-containing receptor in prostate adenocarcinoma. Zhonghua nan ke xue = National journal of andrology. 2007;13(4):324–6.PubMed

44.

Song J, Song Y, Guo W, Jia J, Jin Y, Bai A. Regulatory roles of KDR antisense oligonucleotide on the proliferation of human prostate cancer cell line PC-3. J BUON. 2014;19(3):770–4.PubMed

45.

Schweizer MT, Carducci MA. From bevacizumab to tasquinimod: angiogenesis as a therapeutic target in prostate cancer. Cancer J. 2013;19(1):99–106.CrossRefPubMed

46.

Sherwood BT, Colquhoun AJ, Richardson D, Bowman KJ, O’Byrne KJ, Kockelbergh RC, Symonds RP, Mellon JK, Jones GD. Carbonic anhydrase IX expression and outcome after radiotherapy for muscle-invasive bladder cancer. Clin Oncol. 2007;19(10):777–83.CrossRef

47.

Swinson DE, Jones JL, Richardson D, Wykoff C, Turley H, Pastorek J, Taub N, Harris AL, O’Byrne KJ. Carbonic anhydrase IX expression, a novel surrogate marker of tumor hypoxia, is associated with a poor prognosis in non-small-cell lung cancer. J Clin Oncol. 2003;21(3):473–82.CrossRefPubMed

48.

Bui MH, Seligson D, Han KR, Pantuck AJ, Dorey FJ, Huang Y, Horvath S, Leibovich BC, Chopra S, Liao SY, et al. Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res. 2003;9(2):802–11.PubMed

49.

Ord JJ, Agrawal S, Thamboo TP, Roberts I, Campo L, Turley H, Han C, Fawcett DW, Kulkarni RP, Cranston D, et al. An investigation into the prognostic significance of necrosis and hypoxia in high grade and invasive bladder cancer. J Urol. 2007;178(2):677–82.CrossRefPubMed

50.

Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A, Wilson GD, Turley H, Talks KL, Maxwell PH, et al. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 2000;60(24):7075–83.PubMed

51.

Stewart GD, Nanda J, Brown DJ, Riddick AC, Ross JA, Habib FK. NO-sulindac inhibits the hypoxia response of PC-3 prostate cancer cells via the Akt signalling pathway. Int J Cancer J International du cancer. 2009;124(1):223–32.CrossRef

52.

Pertega-Gomes N, Vizcaino JR, Attig J, Jurmeister S, Lopes C, Baltazar F. A lactate shuttle system between tumour and stromal cells is associated with poor prognosis in prostate cancer. BMC Cancer. 2014;14:352.CrossRefPubMedPubMedCentral

53.

Pertega-Gomes N, Vizcaino JR, Gouveia C, Jeronimo C, Henrique RM, Lopes C, Baltazar F. Monocarboxylate transporter 2 (MCT2) as putative biomarker in prostate cancer. Prostate. 2013;73(7):763–9.CrossRefPubMed

54.

Li Y, Wang H, Oosterwijk E, Selman Y, Mira JC, Medrano T, Shiverick KT, Frost SC. Antibody-specific detection of CAIX in breast and prostate cancers. Biochem Biophys Res Commun. 2009;386(3):488–92.CrossRefPubMedPubMedCentral

55.

Weber DC, Tille JC, Combescure C, Egger JF, Laouiti M, Hammad K, Granger P, Rubbia-Brandt L, Miralbell R. The prognostic value of expression of HIF1alpha, EGFR and VEGF-A, in localized prostate cancer for intermediate- and high-risk patients treated with radiation therapy with or without androgen deprivation therapy. Radiat Oncol. 2012;7:66.CrossRefPubMedPubMedCentral

56.

Denko NC, Fontana LA, Hudson KM, Sutphin PD, Raychaudhuri S, Altman R, Giaccia AJ. Investigating hypoxic tumor physiology through gene expression patterns. Oncogene. 2003;22(37):5907–14.CrossRefPubMed

57.

Chi JT, Wang Z, Nuyten DS, Rodriguez EH, Schaner ME, Salim A, Wang Y, Kristensen GB, Helland A, Borresen-Dale AL, et al. Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med. 2006;3(3), e47.CrossRefPubMedPubMedCentral

58.

Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT, Chi JT, Jeffrey SS, Giaccia AJ. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature. 2006;440(7088):1222–6.CrossRefPubMed

59.

Kirschmann DA, Seftor EA, Fong SF, Nieva DR, Sullivan CM, Edwards EM, Sommer P, Csiszar K, Hendrix MJ. A molecular role for lysyl oxidase in breast cancer invasion. Cancer Res. 2002;62(15):4478–83.PubMed

60.

Peyrol S, Raccurt M, Gerard F, Gleyzal C, Grimaud JA, Sommer P. Lysyl oxidase gene expression in the stromal reaction to in situ and invasive ductal breast carcinoma. Am J Pathol. 1997;150(2):497–507.PubMedPubMedCentral

61.

Trivedy C, Warnakulasuriya KA, Hazarey VK, Tavassoli M, Sommer P, Johnson NW. The upregulation of lysyl oxidase in oral submucous fibrosis and squamous cell carcinoma. J Oral Pathol Med. 1999;28(6):246–51.CrossRefPubMed

62.

Ribeiro R, Monteiro C, Cunha V, Oliveira MJ, Freitas M, Fraga A, Principe P, Lobato C, Lobo F, Morais A, et al. Human periprostatic adipose tissue promotes prostate cancer aggressiveness in vitro. J Exp Clin Cancer Res. 2012;31:32.CrossRefPubMedPubMedCentral

63.

Orr-Urtreger A, Bar-Shira A, Matzkin H, Mabjeesh NJ. The homozygous P582S mutation in the oxygen-dependent degradation domain of HIF-1 alpha is associated with increased risk for prostate cancer. Prostate. 2007;67(1):8–13.CrossRefPubMed

64.

Tanimoto K, Yoshiga K, Eguchi H, Kaneyasu M, Ukon K, Kumazaki T, Oue N, Yasui W, Imai K, Nakachi K, et al. Hypoxia-inducible factor-1alpha polymorphisms associated with enhanced transactivation capacity, implying clinical significance. Carcinogenesis. 2003;24(11):1779–83.CrossRefPubMed

65.

Fransen K, Fenech M, Fredrikson M, Dabrosin C, Soderkvist P. Association between ulcerative growth and hypoxia inducible factor-1alpha polymorphisms in colorectal cancer patients. Mol Carcinog. 2006;45(11):833–40.CrossRefPubMed

66.

Kallio PJ, Pongratz I, Gradin K, McGuire J, Poellinger L. Activation of hypoxia-inducible factor 1alpha: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor. Proc Natl Acad Sci U S A. 1997;94(11):5667–72.CrossRefPubMedPubMedCentral

67.

Wu F, Zhang J, Liu Y, Zheng Y, Hu N. HIF1alpha genetic variants and protein expressions determine the response to platinum based chemotherapy and clinical outcome in patients with advanced NSCLC. Cell Physiol Biochem. 2013;32(6):1566–76.PubMed

68.

Kim HO, Jo YH, Lee J, Lee SS, Yoon KS. The C1772T genetic polymorphism in human HIF-1alpha gene associates with expression of HIF-1alpha protein in breast cancer. Oncol Rep. 2008;20(5):1181–7.PubMed

69.

Wang Y, Zheng Y, Zhang W, Yu H, Lou K, Zhang Y, Qin Q, Zhao B, Yang Y, Hui R. Polymorphisms of KDR gene are associated with coronary heart disease. J Am Coll Cardiol. 2007;50(8):760–7.CrossRefPubMed

70.

Jang MJ, Jeon YJ, Kim JW, Cho YK, Lee SK, Hwang SG, Oh D, Kim NK. Association of VEGF and KDR single nucleotide polymorphisms with colorectal cancer susceptibility in Koreans. Mol Carcinog. 2013;52 Suppl 1:E60–69.CrossRefPubMed

71.

Dong G, Guo X, Fu X, Wan S, Zhou F, Myers RE, Bao G, Burkart A, Yang H, Xing J. Potentially functional genetic variants in KDR gene as prognostic markers in patients with resected colorectal cancer. Cancer Sci. 2012;103(3):561–8.CrossRefPubMed

72.

De Martino M, Klatte T, Seligson DB, LaRochelle J, Shuch B, Caliliw R, Li Z, Kabbinavar FF, Pantuck AJ, Belldegrun AS. CA9 gene: single nucleotide polymorphism predicts metastatic renal cell carcinoma prognosis. J Urol. 2009;182(2):728–34.CrossRefPubMed

73.

Chien MH, Yang JS, Chu YH, Lin CH, Wei LH, Yang SF, Lin CW. Impacts of CA9 gene polymorphisms and environmental factors on oral-cancer susceptibility and clinicopathologic characteristics in Taiwan. PLoS ONE. 2012;7(12), e51051.CrossRefPubMedPubMedCentral

74.

Trackman PC, Bedell-Hogan D, Tang J, Kagan HM. Post-translational glycosylation and proteolytic processing of a lysyl oxidase precursor. J Biol Chem. 1992;267(12):8666–71.PubMed

75.

Uzel MI, Scott IC, Babakhanlou-Chase H, Palamakumbura AH, Pappano WN, Hong HH, Greenspan DS, Trackman PC. Multiple bone morphogenetic protein 1-related mammalian metalloproteinases process pro-lysyl oxidase at the correct physiological site and control lysyl oxidase activation in mouse embryo fibroblast cultures. J Biol Chem. 2001;276(25):22537–43.CrossRefPubMed

76.

Min C, Kirsch KH, Zhao Y, Jeay S, Palamakumbura AH, Trackman PC, Sonenshein GE. The tumor suppressor activity of the lysyl oxidase propeptide reverses the invasive phenotype of Her-2/neu-driven breast cancer. Cancer Res. 2007;67(3):1105–12.CrossRefPubMed

77.

Jeay S, Pianetti S, Kagan HM, Sonenshein GE. Lysyl oxidase inhibits ras-mediated transformation by preventing activation of NF-kappa B. Mol Cell Biol. 2003;23(7):2251–63.CrossRefPubMedPubMedCentral

78.

Min C, Yu Z, Kirsch KH, Zhao Y, Vora SR, Trackman PC, Spicer DB, Rosenberg L, Palmer JR, Sonenshein GE. A loss-of-function polymorphism in the propeptide domain of the LOX gene and breast cancer. Cancer Res. 2009;69(16):6685–93.CrossRefPubMedPubMedCentral

79.

Payne SL, Fogelgren B, Hess AR, Seftor EA, Wiley EL, Fong SF, Csiszar K, Hendrix MJ, Kirschmann DA. Lysyl oxidase regulates breast cancer cell migration and adhesion through a hydrogen peroxide-mediated mechanism. Cancer Res. 2005;65(24):11429–36.CrossRefPubMed

80.

Payne SL, Hendrix MJ, Kirschmann DA. Paradoxical roles for lysyl oxidases in cancer--a prospect. J Cell Biochem. 2007;101(6):1338–54.CrossRefPubMed

81.

Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, Le QT, Giaccia AJ. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell. 2009;15(1):35–44.CrossRefPubMedPubMedCentral

82.

Erler JT, Weaver VM. Three-dimensional context regulation of metastasis. Clin Exp Metastasis. 2009;26(1):35–49.CrossRefPubMed

83.

Kobayashi H, Ishii M, Chanoki M, Yashiro N, Fushida H, Fukai K, Kono T, Hamada T, Wakasaki H, Ooshima A. Immunohistochemical localization of lysyl oxidase in normal human skin. Br J Dermatol. 1994;131(3):325–30.CrossRefPubMed

84.

Wakasaki H, Ooshima A. Immunohistochemical localization of lysyl oxidase with monoclonal antibodies. Lab Investig. 1990;63(3):377–84.PubMed

Title: Genetic polymorphisms in key hypoxia-regulated downstream molecules and phenotypic correlation in prostate cancer
Authors: Avelino Fraga
Ricardo Ribeiro
André Coelho
José Ramon Vizcaíno
Helena Coutinho
José Manuel Lopes
Paulo Príncipe
Carlos Lobato
Carlos Lopes
Rui Medeiros
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: BMC Urology / Issue 1/2017
Electronic ISSN: 1471-2490
DOI: https://doi.org/10.1186/s12894-017-0201-y

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Genetic polymorphisms in key hypoxia-regulated downstream molecules and phenotypic correlation in prostate cancer

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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